Exploratory clinical trial to evaluate the efficacy and safety of transdermal electrical stimulation in patients with central retinal artery occlusion.

PURPOSE: To evaluate the efficacy and safety of transdermal electrical stimulation (TdES) using skin electrodes in patients with central retinal artery occlusion (CRAO). METHODS: Five eyes of five patients with CRAO underwent TdES (10-ms biphasic pulses, 20 Hz, 30 min) six times at 2-week intervals. Only the affected eye was stimulated with 1.0-mA pulses in all patients. The primary endpoint was the best-corrected logMAR visual acuity. The secondary endpoints were changes in the best-corrected logMAR visual acuity, Early Treatment of Diabetic Retinopathy Study (ETDRS) visual acuity, mean deviation of the Humphrey field analyzer (HFA) 10-2, and HFA Esterman test score. We also evaluated its safety. RESULTS: The logMAR visual acuity at 12 weeks was improved by 0.1 or more in two patients and was maintained in two patients compared to the baseline. No obvious changes in the mean logMAR visual acuity, ETDRS visual acuity, mean deviation, and HFA Esterman score were observed at 12 weeks compared to the baseline. All five enrolled patients completed the study according to the protocol. No treatment-related adverse events were observed during this study. CONCLUSION: In this study, logMAR visual acuity was slightly improved in two patients, confirming the safety of TdES. Since CRAO has no established treatment method, further research into the effects of TdES treatment in CRAO patients may be beneficial.

Evaluating the efficacy and safety of transdermal electrical stimulation on the visual functions of patients with retinitis pigmentosa: a clinical trial protocol for a prospective, multicentre, randomised, double-masked and sham-controlled design (ePICO trial).

INTRODUCTION: Previously, we conducted a clinical trial to evaluate the safety and efficacy of transdermal electrical stimulation (TdES) with skin electrodes to improve the visual functions in patients with retinitis pigmentosa (RP). No adverse events were related to the treatment during follow-up examinations, and TdES significantly improved the mean visual acuity and visual field sensitivity. METHODS AND ANALYSIS: We developed a study protocol for a prospective, multicentre, randomised, double-masked and sham-controlled clinical trial, planned to commence on June 2021. We intend to compare the maintenance or improvement in best-corrected visual acuity, and safety of TdES using skin electrodes between patients with RP and the sham group. The primary endpoint comprises the superiority of the logarithm of the minimum angle of resolution (logMAR) visual acuity change at week 24 from baseline in the treatment and sham groups. Secondary endpoints involve the comparison of the treatment and sham groups at week 24 for the logMAR visual acuity, early treatment diabetic retinopathy study visual acuity, the mean deviation value of Humphrey field analyser 10-2, monocular Humphrey Esterman visual field test score, ellipsoid zone length, central foveal thickness and 25-item National Eye Institute Visual Function Questionnaire score. We intend to enrol 50 patients from three Japanese institutions within 1 year and follow them up for 1 years. ETHICS AND DISSEMINATION: The protocol was approved by the institutional review board at the Chiba University Hospital and two other institutions, and was registered with the Japan Registry of Clinical Trials on 17 May 2021. The trial will be conducted in accordance with the principles of the Declaration of Helsinki, and is in accordance with Good Clinical Practice standards. The findings will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: JRCT2032210094.

Improvements of Retinal Sensitivity after Intravitreal Injection of Aflibercept in Eyes with Neovascular Age-Related Macular Degeneration with or without Polypoidal Choroidal Vasculopathy.

PURPOSE: We aim to determine the effects of intravitreal aflibercept (IVA) on the mean sensitivity (MS) of the central retina, best-corrected visual acuity (BCVA), and central foveal thickness (CFT) in eyes with neovascular age-related macular degeneration (nAMD) with or without polypoidal choroidal vasculopathy (PCV). METHODS: This was a prospective, interventional study. All eyes were treatment-naive with nAMD with or without PCV. Each eye received 3 monthly IVA injections followed by an IVA injection every 2 months for 12 months. The primary outcome was the change in the MS within the central 2°. The secondary outcomes were the changes in BCVA, CFT, greatest linear dimension (GLD), and percentage of eyes with a dry macula. RESULTS: Thirty-seven eyes of 37 patients were studied. A significant improvement of the MS (dB) was observed +4.9 ± 4.6 dB (mean ± standard deviation) at 3 M (p < 0.001), +5.5 ± 4.9 dB at 6 (p < 0.001), and +7.0 ± 3.4 dB at 12 M (p < 0.001) compared to the baseline in all eyes. The MS of the eyes with non-PCV was not significantly different from that of eyes with PCV (p = 1.00, 1.00, 1.00, and 0.76 at baseline, 3, 6, and 12 M, respectively). The MS of 11 patients whose BCVA remained unchanged was significantly improved by +6.5 ± 2.8 dB at 3 M (p < 0.001), +6.1 ± 4.3 dB at 6 M (p < 0.001), and +6.4 ± 4.8 dB at 12 M (p = 0.003) compared to the baseline. The mean BCVA was significantly improved from the baseline to 3 M (p < 0.001), 6 M (p = 0.027), and 12 M (p = 0.003) in all eyes. The BCVA was improved or maintained in 97% of the patients at 12 M. The mean CFT and GLD were significantly reduced at 12 M (p < 0.001). Twenty-two eyes (71%) had a dry macula at 12 M. CONCLUSIONS: IVA administered by a fixed dosing regimen led to significant improvements of the central MS, BCVA, and macular morphology at 1 year in eyes with nAMD with or without PCV. These results were not significantly different between eyes with non-PCV and with PCV. The improvements of the MS of the retina of the central 2° in a subgroup whose BCVA remained unchanged through the 12-month experimental period was also significant. We conclude that the MS of the central 2° might be a better marker than the BCVA in determining the effectiveness of IVA treatments and might be helpful in determining early effects on the retina before BCVA changes can be detected.

Effect of darapladib on plasma lipoprotein-associated phospholipase A2 activity in Japanese dyslipidemic patients, with exploratory analysis of a PLA2G7 gene polymorphism of Val279Phe.

BACKGROUND: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is being evaluated as a therapeutic target for treatment of atherosclerosis. This is the first study to examine the effects of darapladib, a novel selective Lp-PLA2 inhibitor, on Lp-PLA2 activity in Japanese dyslipidemic patients with/without the Val279Phe (V279F) single-nucleotide polymorphism (SNP) of the PLA2G7 gene. Exploratory analysis to examine the effects of V279F on Lp-PLA2 inhibition of darapladib was also performed. METHODS AND RESULTS: This was a 4-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging trial of darapladib in 107 Japanese patients with dyslipidemia receiving statins. Patients were randomized to placebo (n=25), darapladib 40 mg (n=28), 80 mg (n=28), or 16 0mg (n=26). All darapladib doses produced sustained dose-dependent inhibition of Lp-PLA2 activity of approximately 49%, 58%, and 67%, respectively (P<0.001 for all comparisons). The inhibitory effect achieved a plateau by 1 week. Patients with the V279F homogenous mutation who have no circulating levels of Lp-PLA2, were excluded from the study. The Lp-PLA2 activity was inhibited in both homozygous wild-type and heterozygote genotypes of the V279F polymorphism subjects to a similar extent, although the heterogeneous mutation has almost half the level of Lp-PLA2 activity compared with that of wild-type in Japanese people. The most common adverse events were odor related. No major safety concerns were noted. CONCLUSIONS: Darapladib produced sustained inhibition of Lp-PLA2 activity in Japanese dyslipidemic patients with/without the V279F SNP of Lp-PLA2.

Long-term safety and efficacy of ambrisentan in Japanese adults with pulmonary arterial hypertension.

OBJECTIVE: To investigate the safety and efficacy of long-term administration of ambrisentan in Japanese adults with pulmonary arterial hypertension (PAH). RESEARCH DESIGN AND METHODS: In this open-label extension of a preceding multicenter dose-escalation study, 21 Japanese patients with PAH received treatment with 5 or 10 mg of ambrisentan once daily and were comprehensively evaluated every 12 weeks. The primary endpoint was the safety of long-term ambrisentan administration, as defined by the incidence and severity of adverse events. The secondary (efficacy) endpoints were change in exercise capacity (as indicated by 6-minute walk distance), World Health Organization functional class, Borg dyspnea index, plasma brain natriuretic peptide level, cardiopulmonary hemodynamics, and time to clinical worsening of PAH. CLINICAL TRIAL REGISTRATION: NCT00554619. RESULTS: The mean total duration of treatment (i.e., including the preceding dose-escalation study) was approximately 139 weeks. There were fewer adverse events related to ambrisentan in this study than in the preceding study, and we identified no new safety signals that might preclude the long-term use of ambrisentan among Japanese adults with PAH. Improvements observed in efficacy endpoints in the preceding study were maintained in the present study. LIMITATIONS: This study did not include a control group and lacked the statistical power to reach definite conclusions regarding the efficacy of ambrisentan. CONCLUSION: Our results suggest that long-term administration of ambrisentan is well tolerated and efficacious for Japanese adults with PAH.

Efficacy, safety, and pharmacokinetics of ambrisentan in Japanese adults with pulmonary arterial hypertension.

OBJECTIVE: To investigate the efficacy, safety, and pharmacokinetics of ambrisentan in Japanese adults with pulmonary arterial hypertension (PAH). RESEARCH DESIGN AND METHODS: In this open-label, uncontrolled, dose-escalation study, 25 Japanese patients with PAH were scheduled to receive 5 mg of ambrisentan once daily for the first 12 weeks, and 10 mg once daily for an additional 12 weeks. The primary endpoint was improvement in exercise capacity from baseline which was indicated by 6-minute walk distance; the secondary endpoints included World Health Organization functional class, Borg dyspnea index, plasma brain natriuretic peptide level, and cardiopulmonary hemodynamics. CLINICAL TRIAL REGISTRATION: NCT00540436. RESULTS: At week 24, improvements were noted in all endpoints, with no clinically significant elevation of serum aminotransferase level. Pharmacokinetics in these Japanese patients was similar to that of non-Japanese populations, suggesting that once-daily dosing is appropriate in Japanese patients. Ambrisentan was generally well tolerated. No new safety signals were identified. LIMITATION: This study lacked a control group and was insufficiently powered to reach definitive conclusions on the efficacy of ambrisentan. CONCLUSION: Ambrisentan is considered as safe and effective for Japanese adults with PAH.

Comments from the Developmental Neurotoxicology Committee of the Japanese Teratology Society on the OECD Guideline for the Testing of Chemicals, Proposal for a New Guideline 426, Developmental Neurotoxicity Study, Draft Document (October 2006 version), and on the Draft Document of the Retrospective Performance Assessment of the Draft Test Guideline 426 on Developmental Neurotoxicity.

In October 2006, a new revision of the draft guideline (OECD Guideline for the Testing of Chemicals, Proposal for a New Guideline 426. Developmental Neurotoxicity Study) and Draft Document of the Retrospective Performance Assessment (RPA) of the Draft Test Guideline 426 on Developmental Neurotoxicity were distributed following incorporation of the results of the Expert Consultation Meeting in Tokyo on May 24-26, 2005. The draft guideline consists of 50 paragraphs and an appendix with 102 references; and the draft RPA consists of 37 paragraphs with 109 references. National coordinators were requested to arrange for national expert reviews of these draft documents in their member countries. Members of the Developmental Neurotoxicology (DNT) Committee of the Japanese Teratology Society (JTS) reviewed, discussed, and commented on the draft Test Guideline Proposal. The DNT Committee of the JTS also commented on the draft document of the RPA. These comments were sent to the OECD Secretariat. The DNT Committee of the JTS expects the comments to be useful for the finalization of these draft documents.

Comments from the Behavioral Teratology Committee of the Japanese Teratology Society on OECD guideline for the testing of chemicals, proposal for a new guideline 426, developmental neurotoxicity study, draft document (September 2003).

In September 2003, a new revision of the draft guideline (Organization for Economic Co-operation and Development [OECD] Guideline for the Testing of Chemicals, Proposal for a New Guideline 426, Developmental Neurotoxicity Study) was distributed. The draft guideline consists of 51 paragraphs and an appendix. The National Coordinators were requested to arrange national expert reviews of the guideline proposal in their member countries. The member of the Behavioral Teratology (BT) Committee of the Japanese Teratology Society (JTS) reviewed, discussed and commented on the draft Test Guideline proposal. The BT Committee of the JTS also commented that the International Collaborative Study to validate this protocol should be definitely performed. These comments were sent to the OECD Secretariat. The BT Committee of the JTS expects that the comments are useful for further discussion.